Process for the synthesis of diesters of phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester

ABSTRACT

An improved process for the preparation of a diester of phosphoric acid 2,5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl ester is described where an alkali metal phosphate is treated with a 3-(chloromethyl)- or 3-(bromomethyl)-5,5-diphenyl-2,4-imidazolidinedione to afford the desired product, as well as valuable intermediates used in the process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C. 371 application based on PCT/US97/05307of Apr. 1, 1997, which claims priority to Provisional Application Ser.No. 60/016,515 of Apr. 30, 1996.

BACKGROUND OF THE INVENTION

The present invention relates to an improved process for the productionof diesters of phosphoric acid2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, which are keyintermediates in the preparation of5,5-diphenyl-[(3-phosphonooxy)methyl]-2,4-imidazolidinedione disodiumsalt (Cerebyx®, also known as fosphenytoin sodium) described in U.S.Pat. Nos. 4,260,769 and 4,925,860, which are herein incorporated byreference. Cerebyx® is useful as an anticonvulsant, antiepileptic, andantiarrhythmic agent.

A synthetic procedure for preparing3-(hydroxymethyl)-5,5-diphenylhydantoin dibenzyl phosphate ester isdisclosed in Varia S. A., et al., Journal of Pharmaceutical Sciences,1984;73:1068-1073. The aforementioned procedure requires the use ofsilver dibenzyl phosphate. This reagent is expensive, light sensitive,and silver byproducts are difficult to remove. Thus, special proceduresare required to purify the desired product.

Metal salts of dialkyl phosphates have been used for phosphorylation ofalkyl halides, and in general, the cation of choice is silver (Sasse K.,"Methoden der Organisation Chemis" (Houben-Weyl), Band XLI/2, ThiemeVerlag, Stuttgart, 1964:302-306). Precipitation of silver halide fromthe reaction mixture drives the reaction to completion. Salts of dialkylphosphates with sodium or potassium as the gegenion have been used withsome substrates, but are generally considered to be very poornucleophiles for reaction with alkyl halides (Khorana H. G., "SomeRecent Developments in the Chemistry of Phosphates of BiologicalInterest," John Wiley & Sons, New York, N.Y., 1961:13-14; Zwierak A, andKluba M., Tetrahedron, 1971;27:3163-3170; U.S. Pat. Nos. 2,494,126,2,494,283, and 2,494,284). In point of fact, Zwierzak A. and Kluba M.,Tetrahedron, 1971;27:3163-3170 disclose that sodium or potassium saltsof dialkyl phosphates are too unreactive to give satisfactoryphosphorylation.

We have surprisingly and unexpectedly found that alkali metal phosphateesters react with either 3-(chloromethyl)- or3-(bromomethyl)-5,5-diphenyl-2,4-imidazolidinedione to afford diestersof phosphoric acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester.The object of the present invention is an improved, short, efficient,and economical process that can be carried out on a manufacturing scalefor the preparation of diesters of phosphoric acid2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester. Thus, the presentprocess avoids the use of costly and unstable reagents such as silverphosphate esters and associated silver by-products, which are difficultto remove and is amenable to large-scale synthesis.

SUMMARY OF THE INVENTION

Accordingly, a first aspect of the present invention is an improvedprocess for the preparation of a compound of Formula I ##STR1## whereinR is aryl, arylalkyl, or

alkyl;

which comprises treating a compound of Formula II ##STR2## wherein X ischloro or bromo with a compound of Formula III ##STR3## wherein M is analkali metal, and R is as defined above in a solvent to afford acompound of Formula I.

A second aspect of the present invention is a novel intermediate ofFormula I ##STR4## wherein R is aryl, arylalkyl, or

alkyl with the exclusion of:

phosphoric acid dibenzyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of Formula I, the term "alkyl" means a straight orbranched hydrocarbon radical having from 1 to 6 carbon atoms andincludes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "aryl" means an aromatic radical which is a phenyl group, anaphthyl group, unsubstituted or substituted by 1 to 4 substituentsselected from alkyl as defined above, nitro or halogen.

The term "arylalkyl" means an aromatic radical attached to an alkylradical wherein aryl and alkyl are as defined above, for example, benzyland the like.

"Halogen" is fluorine, chlorine, bromine, or iodine.

"Alkali metal" is a metal in Group IA of the periodic table andincludes, for example, lithium, sodium, potassium, cesium, and the like.

The process of the present invention is a new, improved, economical, andcommercially feasible method for preparing compounds of Formula I, whichare useful as intermediates in the preparation of fosphenytoin sodium,which is useful as an anticonvulsant, antiepileptic, and antiarrhythmicagent.

The process of the present invention is outlined in the followingscheme: ##STR5##

A compound of Formula I wherein R is aryl, arylalkyl, or alkyl isprepared by reacting a compound of Formula II wherein X is chlorine orbromine with a compound of Formula III wherein M is an alkali metal suchas, for example, lithium, sodium, potassium, cesium, and the like, and Ris as defined above in a solvent such as, for example, acetonitrile andthe like at about 25° C. to about the reflux temperature of the solventfor about 1 hour to about 24 hours to afford a compound of Formula I.When M is potassium, optionally a catalytic amount of potassium iodidemay be used. When M is sodium, optionally a catalytic amount oftetrabutylammonium iodide or 18-crown-6 may be used. Preferably, thereaction is carried out in acetonitrile at reflux for about 2 hours toabout 11 hours.

5,5-Diphenyl-2,4-imidazolidinedione (phenytoin) is readily available ormay be prepared according to procedures disclosed in U.S. Pat. No.2,409,154.

Compounds of Formula III are either known or capable of being preparedby methods known in the art.

The following examples are illustrative to show the present process, thepreparation of starting materials, and the use of a compound of FormulaI obtained by the present process to prepare5,5-diphenyl-[(3-phosphonooxy)methyl]-2,4-imidazolidinedione disodiumsalt useful as an anticonvulsant, antiepileptic, and antiarrhythmicagent.

EXAMPLE 1 Phosphoric Acid Dibenzyl Ester2,5-Dioxo-4,4-diphenyl-1-imidazolidin-1-ylmethyl Ester

Step (A): Preparation of3-(Chloromethyl)-5,5-diphenyl-2.4-imidazolidinedione

A mixture of 250 kg 5,5-diphenyl-2,4-imidazolidinedione (phenytoin), 2.6kg of potassium carbonate, and 454 L ethyl alcohol is heated to 70° C.to 80° C. One hundred twenty-five kilograms of 37% formaldehyde solutionis added, and heating is continued for at least 2 hours. The reactionmixture is cooled slowly, and 600 L of water is added during the coolingcycle. The resulting slurry is cooled to less than 25° C. The product,3-hydroxymethyl-5,5-diphenyl-2,4-imidazolidinedione, is collected byfiltration and washed with water. The wet cake is dried at 20° C. to 50°C. The dried product and 1350 kg of ethyl acetate are charged to areactor. Five kilograms of dimethyl formamide and 135 kg of thionylchloride are added at 25° C. to 35° C. The reaction mixture is heated to35° C. to 60° C. for about 2 hours or until the reaction is essentiallycomplete. The reaction mixture is cooled to 20° C. to 30° C. andcombined with 2200 L of aqueous sodium bicarbonate. The organic layer isseparated and concentrated by distillation. Heptane is added, and theresulting slurry is cooled. The title compound is collected byfiltration and washed with heptane. The wet cake is dried at 20° C. to50° C. under vacuum to give3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione, 268 kg (90%yield); mp 161.2-161.8° C.

Step (B): Preparation of Phosphoric Acid Dibenzyl Ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl Ester

Method A

A mixture of 250 kg 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedionefrom Step (A), 270 kg of potassium dibenzyl phosphate, 6 kg of potassiumcarbonate, 0.75 kg of potassium iodide, and 500 kg of acetonitrile isheated at 70° C. to reflux for 2 to 5 hours or until the reaction isessentially complete. The reaction mixture is cooled to 40° C. to 65° C.and filtered. The solution is stirred with at least 11 kg of activatedcarbon and filtered using a filter-aid. The reaction solvent is replacedby adding toluene in portions and vacuum distilling. The resultingslurry is cooled to less than 5° C. The title compound is collected byfiltration and washed with cold toluene. The wet cake is dried at 50° C.under vacuum to give phosphoric acid dibenzyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester, 315 kg (70%yield); mp 118.6-119.7° C.

Method B

Ten grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione fromStep (A), 10.3 g of sodium dibenzyl phosphate, and 0.5 g of sodiumcarbonate were slurried into 50 mL acetonitrile. The reaction mixturewas heated at reflux for 11 hours. The solution was filtered to removesodium chloride precipitate. The filtrate volume was reduced undervacuum, then 40 mL of toluene added. The solution was seeded and cooledto 0° C. The product was filtered and dried under vacuum at 40° C. 7.38Grams of the title compound was obtained (43% yield)(product identicalwith Method A product by high pressure liquid chromatography(HPLC)retention time).

Method C

Ten grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione fromStep (A), 14 g of cesium dibenzyl phosphate, and 0.48 g of cesiumcarbonate were slurried into 50 mL acetonitrile. The reaction mixturewas heated at reflux for 4 hours. The solution was filtered to removecesium chloride precipitate. The filtrate volume was reduced undervacuum. The solution was seeded and cooled to 0° C. The product wasfiltered and dried under vacuum at 40° C. 11.5 Grams of the titlecompound was obtained (63.9% yield)(product identical with Method Aproduct by HPLC retention time).

EXAMPLE 2 Phosphoric Acid 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylEster Dimethyl Ester

Thirty grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedionefrom Step (A), 17.1 g of potassium dimethyl phosphate, 0.6 g ofpotassium carbonate, and 0.15 g of potassium iodide were slurried into75 mL of acetonitrile. The reaction mixture was heated at reflux for 3hours. The solution was filtered to remove potassium chlorideprecipitate and concentrated to thick oil. Isopropyl alcohol was addedto the oil and cooled to 0° C. The product was filtered and dried undervacuum. Sixteen grams of the title compound was obtained (40.9% yield);mp 123.1-124.3° C. Proton nuclear magnetic resonance spectroscopy (¹ HNMR) deuterated dimethyl sulfoxide (DMSO-d₆): 3.6 ppm (d, 6H), 5.3 (d,2H), 7.3-7.5 (m, 10H), 10.0 (s, 1H); doublets from long rangephosphorous coupling.

EXAMPLE 3 Phosphoric Acid Dibutyl Ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl Ester

23.1 Grams of di(n-butyl)phosphate and 6.2 g of potassium hydroxide wereslurried into 100 mL of t-butyl methyl ether. The reaction was stirreduntil homogeneous and concentrated under vacuum to thick oil ofpotassium di(n-butyl)phosphate. The oil, along with 30 g of3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione from Step (A), 0.6g of potassium carbonate, and 0.15 g of potassium iodide was slurriedinto 75 mL of acetonitrile. The reaction mixture was heated at refluxfor 2.5 hours. The solution was filtered to remove potassium chlorideprecipitate and then concentrated under vacuum. The residue wascrystallized from ethyl acetate/heptane to give 32.8 g of the titlecompound (69.2% yield); mp 94.8-96.9° C. ¹ H NMR (DMSO-d₆): 0.8 ppm (t,3H), 1.2 (dq, 2H), 1.45 (dt, 2H), 3.85 (dq, 2H), 5.3 (d, 2H), 7.3-7.5(m, 10H), 9.8 (s, 1H) (peaks at 3.85 and 5.3 doublets from long rangephosphorus coupling).

EXAMPLE 4 Phosphoric Acid di-tert-butyl Ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl Ester

35.5 Grams of 3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione fromStep (A), 30.7 g of potassium di(t-butyl) phosphate, 0.6 g of potassiumcarbonate, and 0.15 g of potassium iodide were slurried into 200 mLacetonitrile. The reaction mixture was heated at reflux for 2.5 hours.The solution was filtered to remove potassium chloride precipitate. Thefiltrate was cooled to 0° C. and filtered to give 22.3 g of the titlecompound (38.6% yield); mp 108.5° C. (d). ¹ H NMR (DMSO-d₆): 1.3 ppm (s,18H), 5.2 (d, 2H), 7.3-7.5 (m, 10H), 9.9 (s, 1H); doublet from longrange phosphorus coupling.

EXAMPLE 5 5,5-Diphenyl-[(3-phosphonooxy)methyl]-2,4-imidazolidinedioneDisodium Salt

A mixture of 250 kg phosphoric acid dibenzyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester (Example 1, Step(B)), 9 kg of activated carbon (optionally filter-aid may be added), and1025 L of acetone is heated at a temperature range of 45° C. to reflux.The activated carbon is removed by filtration. The filtrate is chargedto a hydrogenator containing about 6.6 kg of palladium on carbon (50%water wet), and the total water is adjusted to about 28 L. Thehydrogenation is run at 20° C. to 40° C. and continued until hydrogenuptake diminishes. The mixture is filtered to remove the catalyst. Aminimum of 700 L of water is added, and the solution is concentrated byvacuum distillation at a pot temperature of less than 60° C. The pH ofthe solution is adjusted to 8.2 to 8.9 with dilute aqueous sodiumhydroxide and dilute hydrochloric acid while maintaining a solutiontemperature of 20° C. to 35° C. At least 27.5 kg of activated carbon isadded to the solution. The solution is filtered using a filter-aid.Acetone is added, and the resulting slurry is cooled. The product iscollected by filtration, washed with acetone, and dried at 20° C. to 25°C. under vacuum to give the title compound 168 kg (90% yield) on ananhydrous basis. ¹ H NMR deuterated water (D₂ O): 5.2 ppm (d, 2H),7.35-7.5 (m, 10H); NH proton exchanged in D₂ O, doublet from long rangephosphorus coupling.

We claim:
 1. A process for the preparation of a compound of Formula I##STR6## wherein R is aryl, arylalkyl, oralkyl;which comprises reactinga compound of Formula II ##STR7## wherein X is chloro or bromo with acompound of Formula III ##STR8## wherein M is an alkali metal, and R isas defined above in a solvent to afford a compound of Formula I.
 2. Aprocess according to claim 1 wherein the solvent is acetonitrile.
 3. Aprocess according to claim 1 for the preparation of a compound selectedfrom the group consisting of:Phosphoric acid dibenzyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester; Phosphoric acid2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester dimethyl ester;Phosphoric acid dibutyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester; and Phosphoricacid di-tert-butyl ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylester.
 4. A process according to claim 3 for the preparation ofphosphoric acid dibenzyl ester2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethyl ester.
 5. A processaccording to claim 1 wherein the compound of Formula II is3-(chloromethyl)-5,5-diphenyl-2,4-imidazolidinedione.
 6. A processaccording to claim 1 wherein a compound of Formula III is selected fromthe group consisting of: potassium dibenzyl phosphate: sodium dibenzylphosphate; cesium dibenzyl phosphate; potassium dimethyl phosphate;sodium dimethyl phosphate; cesium dimethyl phosphate; potassiumdi(n-butyl) phosphate; sodium di(n-butyl) phosphate; potassium(di(t-butyl) phosphate; sodium di(t-butyl) phosphate; and cesiumdi(t-butyl) phosphate.
 7. A process according to claim 6 wherein thecompound of Formula III is potassium dibenzyl phosphate.